Immune transcriptomes of highly exposed SARS-CoV-2 asymptomatic seropositive versus seronegative individuals from the Ischgl community

AbstractSARS-CoV-2 infection ranges from asymptomatic to severe with lingering symptomatology in some. This prompted investigation of whether or not asymptomatic disease results in measurable immune activation post-infection. Immune activation following asymptomatic SARS-CoV-2 infection was characterized through a comparative investigation of the immune cell transcriptomes from 43 asymptomatic seropositive and 52 highly exposed seronegative individuals from the same community 4–6 weeks following a superspreading event. Few of the 95 individuals had underlying health issues. One seropositive individual reported Cystic Fibrosis and one individual reported Incontinentia pigmenti. No evidence of immune activation was found in asymptomatic seropositive individuals with the exception of the Cystic Fibrosis patient. There were no statistically significant differences in immune transcriptomes between asymptomatic seropositive and highly exposed seronegative individuals. Four positive controls, mildly symptomatic seropositive individuals whose blood was examined 3 weeks following infection, showed immune activation. Negative controls were four seronegative individuals from neighboring communities without COVID-19. All individuals remained in their usual state of health through a five-month follow-up after sample collection. In summary, whole blood transcriptomes identified individual immune profiles within a community population and showed that asymptomatic infection within a super-spreading event was not associated with enduring immunological activation.

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Immune transcriptomes of highly exposed SARS-CoV-2 asymptomatic seropositive versus seronegative individuals from the Ischgl community

10.21203/rs.3.rs-69657/v1 ◽

2020 ◽

Author(s):

Hye Kyung Lee ◽

Ludwig Knabl ◽

Lisa Pipperger ◽

Andre Volland ◽

Priscilla Furth ◽

...

Keyword(s):

Genetic Disease ◽

Nuclear Factor Kappa B ◽

Immune Cell ◽

Immunological Response ◽

Asymptomatic Infection ◽

Health Issues ◽

Immunological Activation ◽

Usual State ◽

Positive Controls

Abstract To investigate prevalence of ongoing activation of inflammation following asymptomatic SARS-CoV-2 infection we characterized immune cell transcriptomes from 43 asymptomatic seropositive and 52 highly exposed seronegative individuals with few underlying health issues following a community superspreading event. Four mildly symptomatic seropositive individuals examined three weeks after infection as positive controls demonstrated immunological activation. Approximately four to six weeks following the event, the two asymptomatic groups showed no significant differences. Two seropositive patients with underlying genetic disease impacting immunological activation were included (Cystic Fibrosis (CF), Nuclear factor-kappa B Essential Modulator (NEMO) deficiency). CF, but not NEMO, associated with significant immune transcriptome differences including some associated with severe SARS-CoV-2 infection (IL1B, IL17A, respective receptors). All subjects remained in their usual state of health from event through five-month follow-up. Here, asymptomatic infection resolved without evidence of prolonged immunological activation. Inclusion of subjects with underlying genetic disease illustrated the pathophysiological importance of context on impact of immunological response.

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Immune transcriptomes of highly exposed SARS-CoV-2 asymptomatic seropositive versus seronegative individuals from the Ischgl community

10.1101/2020.09.01.20185884 ◽

2020 ◽

Author(s):

Hye Kyung Lee ◽

Ludwig Knabl ◽

Lisa Pipperger ◽

Andre Volland ◽

Priscilla A. Furth ◽

...

Keyword(s):

Genetic Disease ◽

Nuclear Factor Kappa B ◽

Immune Cell ◽

Immunological Response ◽

Asymptomatic Infection ◽

Health Issues ◽

Immunological Activation ◽

Usual State ◽

Positive Controls

To investigate prevalence of ongoing activation of inflammation following asymptomatic SARS-CoV-2 infection we characterized immune cell transcriptomes from 43 asymptomatic seropositive and 52 highly exposed seronegative individuals with few underlying health issues following a community superspreading event. Four mildly symptomatic seropositive individuals examined three weeks after infection as positive controls demonstrated immunological activation. Approximately four to six weeks following the event, the two asymptomatic groups showed no significant differences. Two seropositive patients with underlying genetic disease impacting immunological activation were included (Cystic Fibrosis (CF), Nuclear factor-kappa B Essential Modulator (NEMO) deficiency). CF, but not NEMO, associated with significant immune transcriptome differences including some associated with severe SARS-CoV-2 infection (IL1B, IL17A, respective receptors). All subjects remained in their usual state of health from event through five-month follow-up. Here, asymptomatic infection resolved without evidence of prolonged immunological activation. Inclusion of subjects with underlying genetic disease illustrated the pathophysiological importance of context on impact of immunological response.

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Deletion of cftr leads to an excessive neutrophilic response and defective tissue repair in a zebrafish model of sterile inflammation

10.1101/842195 ◽

2019 ◽

Cited By ~ 1

Author(s):

Audrey Bernut ◽

Catherine A. Loynes ◽

R. Andres Floto ◽

Stephen A. Renshaw

Keyword(s):

Cystic Fibrosis ◽

Tissue Repair ◽

Cell Function ◽

Immune Cell ◽

Genetic Disorder ◽

Innate Immune ◽

Lung Damage ◽

Tanshinone Iia ◽

Sterile Inflammation ◽

Inflammatory Status

AbstractInflammation-related progressive lung destruction is the leading causes of premature death in cystic fibrosis (CF), a genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. However, therapeutic targeting of inflammation has been hampered by a lack of understanding of the links between a dysfunctional CFTR and the deleterious innate immune response in CF. Herein, we used CFTR-depleted zebrafish larvae as an innovative in vivo vertebrate model, mimicking aspects of the inflammatory pathology of CF-related lung, to understand how CFTR dysfunction leads to abnormal inflammatory status in CF.We show that impaired CFTR-mediated inflammation correlates with an exuberant neutrophilic response after injury: CF zebrafish exhibit enhanced and sustained accumulation of neutrophils at wounds. Excessive epithelial oxidative responses drive enhanced neutrophil recruitment towards wounds. Persistence of neutrophils at inflamed sites is associated with impaired reverse migration of neutrophils and reduction in neutrophil apoptosis. As a consequence, the increased number of neutrophils at wound sites causes tissue damage and abnormal tissue repair. Importantly, the pro-resolution molecule Tanshinone IIA successfully re-balances inflammation both by accelerating inflammation resolution and by improving tissue repair in CFTR-deficient animal.Larval zebrafish giving a unique insight into innate immune cell function in CFTR deficiency, our findings bring important new understanding of the mechanisms underlying the inflammatory pathology in CF, which could be addressed therapeutically to prevent inflammatory lung damage in CF patients with potential improvements in disease outcomes.

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Abstract MP41: A Role Of Isolevuglandins In Systemic Lupus Erythematosus Associated Autoimmunity And Hypertension

Hypertension ◽

10.1161/hyp.76.suppl_1.mp41 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

David M Patrick ◽

Nestor de la Visitacion ◽

Michelle J Ormseth ◽

Charles Stein ◽

Sean S Davies ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Immune Activation ◽

Lupus Erythematosus ◽

Cell Activation ◽

Immune Cell ◽

Healthy Controls ◽

Systemic Lupus ◽

Immune Cell Activation ◽

Systemic Immune Activation

Essential hypertension and systemic lupus erythematosus (SLE) are devastating conditions that disproportionately affect women. SLE has heterogeneous manifestations and treatment is limited to the use of non-specific global immunosuppression. Importantly, there is an increased prevalence of hypertension in women with SLE compared to healthy controls. Isolevuglandins (IsoLGs) are oxidation products of fatty acids that form as a result of reactive oxygen species. These molecules adduct covalently to lysine residues of proteins. Adducted proteins are then presented as autoantigens to T-cells resulting in immune cell activation. Previous studies have shown an essential role of IsoLGs in immune cell activation and the development of hypertension in animal models. We hypothesize that isoLGs are important for the development of hypertension and systemic immune activation in SLE. We first examined isoLG adduct accumulation within monocytes of human subjects with SLE compared to healthy controls. By flow cytometry, we found marked accumulation of isoLG adducts within CD14 + monocytes (34.2% ± 12.4% vs 3.81% ± 2.1% of CD14 + , N = 10-11, P <0.05). We confirmed this increase in isoLG adducts by mass spectrometry. To determine a causative role of isoLG adducts in immune activation and hypertension in SLE, we employed the B6.SLE123 and NZBWF1 mouse models of SLE. Animals were treated with the isoLG scavenger 2-hydroxybenzylamine (2-HOBA) or vehicle beginning at 7 weeks and were sacrificed at 32 weeks of age. C57BL/6 and NZW were used as controls. Importantly, treatment with 2-HOBA attenuated blood pressure in both mouse models (systolic BP 136.2 ± 5.6 mmHg for B6.SLE123 vs 120.9 ± 4.46 mmHg for B6.SLE123 +2HOBA; 164.7 ± 24.4 mmHg for NZBWF1 vs 136.9 ± 14.9 mmHg for NZBWF1 +2HOBA, N = 6-8, P < 0.05). Moreover, treatment with 2-HOBA reduced albuminuria and renal injury in the B6.SLE123 model (albumin/creatinine ratio 33.8 ± 2.0 x 10 -2 μg/mg for B6.SLE123 vs 5.5 ± 0.9 x 10 -2 μg/mg for B6.SLE123 +2HOBA, N = 7-9, P < 0.05). Finally, immune cell accumulation in primary and secondary lymphoid organs is significantly attenuated by 2-HOBA. These studies suggest a critical role of isoLG adduct accumulation in both systemic immune activation and hypertension in SLE.

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Reduction of leucocyte cell surface disulfide bonds during immune activation is dynamic as revealed by a quantitative proteomics workflow (SH-IQ)

Open Biology ◽

10.1098/rsob.180079 ◽

2018 ◽

Vol 8 (9) ◽

pp. 180079

Author(s):

Monika Stegmann ◽

A. Neil Barclay ◽

Clive Metcalfe

Keyword(s):

Immune System ◽

Cell Surface ◽

Immune Activation ◽

Disulfide Bonds ◽

Cell Function ◽

Immune Cell ◽

Surface Proteins ◽

Cell Surface Receptors ◽

Surface Receptors ◽

Pathogen Clearance

Communication through cell surface receptors is crucial for maintaining immune homeostasis, coordinating the immune response and pathogen clearance. This is dependent on the interaction of cell surface receptors with their ligands and requires functionally active conformational states. Thus, immune cell function can be controlled by modulating the structure of either the receptor or the ligand. Reductive cleavage of labile disulfide bonds can mediate such an allosteric change, resulting in modulation of the immune system by a hitherto little studied mechanism. Identifying proteins with labile disulfide bonds and determining the extent of reduction is crucial in elucidating the functional result of reduction. We describe a mass spectrometry-based method—thiol identification and quantitation (SH-IQ)—to identify, quantify and monitor such reduction of labile disulfide bonds in primary cells during immune activation. These results provide the first insight into the extent and dynamics of labile disulfide bond reduction in leucocyte cell surface proteins upon immune activation. We show that this process is thiol oxidoreductase-dependent and mainly affects activatory (e.g. CD132, SLAMF1) and adhesion (CD44, ICAM1) molecules, suggesting a mechanism to prevent over-activation of the immune system and excessive accumulation of leucocytes at sites of inflammation.

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Comparative Replication and Immune Activation Profiles of SARS-CoV-2 and SARS-CoV in Human Lungs: An Ex Vivo Study With Implications for the Pathogenesis of COVID-19

Clinical Infectious Diseases ◽

10.1093/cid/ciaa410 ◽

2020 ◽

Vol 71 (6) ◽

pp. 1400-1409 ◽

Cited By ~ 180

Author(s):

Hin Chu ◽

Jasper Fuk-Woo Chan ◽

Yixin Wang ◽

Terrence Tsz-Tai Yuen ◽

Yue Chai ◽

...

Keyword(s):

Immune Activation ◽

Human Lung ◽

Ex Vivo ◽

Clinical Manifestations ◽

Asymptomatic Infection ◽

Replication Capacity ◽

Cell Tropism ◽

Human Lungs ◽

Activation Profile ◽

Underlying Mechanisms

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging coronavirus that has resulted in more than 2 000 000 laboratory-confirmed cases including over 145 000 deaths. Although SARS-CoV-2 and SARS-CoV share a number of common clinical manifestations, SARS-CoV-2 appears to be highly efficient in person-to-person transmission and frequently causes asymptomatic or presymptomatic infections. However, the underlying mechanisms that confer these viral characteristics of high transmissibility and asymptomatic infection remain incompletely understood. Methods We comprehensively investigated the replication, cell tropism, and immune activation profile of SARS-CoV-2 infection in human lung tissues with SARS-CoV included as a comparison. Results SARS-CoV-2 infected and replicated in human lung tissues more efficiently than SARS-CoV. Within the 48-hour interval, SARS-CoV-2 generated 3.20-fold more infectious virus particles than did SARS-CoV from the infected lung tissues (P < .024). SARS-CoV-2 and SARS-CoV were similar in cell tropism, with both targeting types I and II pneumocytes and alveolar macrophages. Importantly, despite the more efficient virus replication, SARS-CoV-2 did not significantly induce types I, II, or III interferons in the infected human lung tissues. In addition, while SARS-CoV infection upregulated the expression of 11 out of 13 (84.62%) representative proinflammatory cytokines/chemokines, SARS-CoV-2 infection only upregulated 5 of these 13 (38.46%) key inflammatory mediators despite replicating more efficiently. Conclusions Our study provides the first quantitative data on the comparative replication capacity and immune activation profile of SARS-CoV-2 and SARS-CoV infection in human lung tissues. Our results provide important insights into the pathogenesis, high transmissibility, and asymptomatic infection of SARS-CoV-2.

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Patient acceptance and outcome of mental health screening in Swedish adults with cystic fibrosis

Quality of Life Research ◽

10.1007/s11136-020-02417-5 ◽

2020 ◽

Vol 29 (6) ◽

pp. 1579-1585 ◽

Cited By ~ 2

Author(s):

Stina Järvholm ◽

Petrea Ericson ◽

Marita Gilljam

Keyword(s):

Mental Health ◽

Cystic Fibrosis ◽

Mental Health Problems ◽

International Committee ◽

Patient Acceptance ◽

Annual Review ◽

First Year ◽

Health Issues ◽

Screening Process ◽

Annual Screening

Abstract Purpose Anxiety and depression are common among adults with cystic fibrosis (CF), and the International Committee on Mental Health in CF (ICMH) recommends annual screening for mental health problems. We implemented screening according to the recently published guidelines and assessed the results from the first year, as well as the patients’ attitude to annual screening Methods Adult patients attending Gothenburg CF-center from Feb 2015 to Dec 2016 completed the GAD-7 (anxiety) and PHQ-9 (depression) forms at the time of their annual review. In addition, questions regarding the screening process and instruments used were asked. Results All invited patients (n = 100, 52% males, 2% lung transplanted), with a median age of 28 years (range 18–65), agreed to participate. In general (83%), the patients were positive to screening on an annual basis. No significant differences in total GAD-7 and PHQ-9 scores were found when comparing men and women. Patients younger than 30 years of age reported more symptoms of anxiety compared to older patients (p = 0.02). There were 21 (21%) patients with scores > 10 for GAD-7 and/or PHQ-9 indicating at least moderate anxiety or depression. Scores > 10 were reported by 15 patients on GAD-7, 15 patients on PHQ-9, and 9 patients reported scores above 10 on both measures. Conclusion The patients considered annual check-ups for mental health issues important. Although the screening results are reassuring, the group is heterogenic and younger individuals should be given extra attention. Follow-up over longer time will provide more robust data.

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Plant-derived oleanolic acid ameliorates markers of subclinical inflammation and innate immunity activation in diet-induced pre-diabetic rats

Therapeutic Advances in Endocrinology and Metabolism ◽

10.1177/2042018820935771 ◽

2020 ◽

Vol 11 ◽

pp. 204201882093577

Author(s):

Mlindeli Gamede ◽

Lindokuhle Mabuza ◽

Phikelelani Ngubane ◽

Andile Khathi

Keyword(s):

Cell Count ◽

Oleanolic Acid ◽

Proinflammatory Cytokines ◽

Immune Activation ◽

Molecular Mechanisms ◽

Dietary Intervention ◽

Immune Cell ◽

Diabetic Rats ◽

Sprague Dawley ◽

Cell Counts

Aims: Sub-clinical inflammation during pre-diabetes is one of the predisposing factors that facilitates the progression of pre-diabetes to type 2 diabetes. The administration of oleanolic acid (OA) with or without dietary intervention ameliorates the metabolic and cardiovascular complications in diet-induced pre-diabetes animal models of pre-diabetes. This study aimed to investigate whether OA can also suppress immune activation and ameliorate pro-inflammatory markers. Methods: Pre-diabetes was induced by feeding Sprague Dawley rats a high-fat high carbohydrate diet for 20 weeks. The pre-diabetic rats were then treated with OA (80 mg/kg) or metformin (500 mg/kg) in the presence or absence of dietary interventions for a period of 12 weeks. At the end of the treatment period, the animals were euthanised and whole blood was used for platelet and immune cell count while plasma was used for fibrinogen, cluster differentiation 40 ligand and pro-inflammatory cytokine evaluation. Results: The results of this study revealed that OA, with or without dietary intervention, improved lipid metabolism by restoring high-density lipoprotein (HDL) and low-density lipoproteins (LDLs) as well as reducing platelets and immune cell counts. Furthermore, OA also decreased plasma proinflammatory cytokines, including tumour necrosis factor-α and -1β. Markers of immune activation such as C-reactive protein, fibrinogen, and CD40L were also decreased upon administration of OA with or without dietary intervention. Conclusion: The findings of this study suggest that OA may provide an alternative to prevent the progression of pre-diabetes to overt diabetes. This was evident by the reduction of differential white blood cell count and proinflammatory cytokines that exercebate insulin resistance. However, more studies are needed to elucidate the molecular mechanisms and to improve efficacy.

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Identification of distinct immune activation profiles in adult humans

Scientific Reports ◽

10.1038/s41598-020-77707-6 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Renaud Cezar ◽

Audrey Winter ◽

Delphine Desigaud ◽

Manuela Pastore ◽

Lucy Kundura ◽

...

Keyword(s):

T Cells ◽

Immune Activation ◽

Cell Activation ◽

Immune Cell ◽

Nk Cell ◽

Liver Steatosis ◽

Treg Cells ◽

Microbial Translocation ◽

Color Flow

AbstractLatent infectious agents, microbial translocation, some metabolites and immune cell subpopulations, as well as senescence modulate the level and quality of activation of our immune system. Here, we tested whether various in vivo immune activation profiles may be distinguished in a general population. We measured 43 markers of immune activation by 8-color flow cytometry and ELISA in 150 adults, and performed a double hierarchical clustering of biomarkers and volunteers. We identified five different immune activation profiles. Profile 1 had a high proportion of naïve T cells. By contrast, Profiles 2 and 3 had an elevated percentage of terminally differentiated and of senescent CD4+ T cells and CD8+ T cells, respectively. The fourth profile was characterized by NK cell activation, and the last profile, Profile 5, by a high proportion of monocytes. In search for etiologic factors that could determine these profiles, we observed a high frequency of naïve Treg cells in Profile 1, contrasting with a tendency to a low percentage of Treg cells in Profiles 2 and 3. Moreover, Profile 5 tended to have a high level of 16s ribosomal DNA, a direct marker of microbial translocation. These data are compatible with a model in which specific causes, as the frequency of Treg or the level of microbial translocation, shape specific profiles of immune activation. It will be of interest to analyze whether some of these profiles drive preferentially some morbidities known to be fueled by immune activation, as insulin resistance, atherothrombosis or liver steatosis.

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